Alzheimer disease (AD) imposes a substantial societal burden. Clinical AD likely results through the interaction of 3 factors: reserve, AD- and vascular pathology. Brain MRI and cognitive tests can identify proxy measures of reserve and subclinical markers (heritable endophenotypes) of AD- and vascular pathology. Neurotrophic factors (NTF) promote neuronal survival and function and are possible key determinants of reserve, the capacity that allows some persons to tolerate greater brain pathology without clinical symptoms. NTF also impact AD- and ischemia-related pathological processes. Experimental and clinical data suggest that circulating NTF levels are increased by a healthy diet and exercise, and decline with age. However, no prior study has comprehensively examined the clinical and genetic correlates of NTF in a community-based sample, or the association of NTF with brain aging and clinical AD. We hypothesize that genetic variation in the NTF pathway will be related to variation in serum NTF levels, and that lower circulating NTF levels will be associated with lower reserve, more cross-sectional evidence of brain aging on MRI and cognitive testing, greater longitudinal decline in these measures, and a higher risk of clinical dementia and AD. We propose to genotype a comprehensive panel of NTF and NTF receptors and measure serum levels of three NTF: brain derived neurotrophic factor (BDNF), nerve growth factor (NGF), and vascular endothelial growth factor (VEGF) in the large, middle-aged to elderly, community-based, Framingham Heart Study (FHS) Original, Offspring and Omni cohorts. Serum levels of IGF1 have been measured by a collaborator. DNA, brain MRI and cognitive test measures are already available. We offer the following, interlinked specific aims: Aim 1: To examine the clinical and genetic correlates of NTF in all 3 FHS cohorts. Aim 2: To relate NTF serum levels and genetic variation in NTF pathway genes to cross-sectional measures on brain MRI and cognitive tests in the FHS Offspring and Omni cohorts. Aim 3: To prospectively relate baseline serum levels and genetic variation in NTF pathway genes to longitudinal changes in MRI and cognitive tests in the FHS Offspring and Omni. Aim 4: To prospectively relate baseline serum concentrations of NTF (measured in stored sera from 1992-94) and genetic variation in NTF pathway genes to risk of incident dementia and AD over a follow-up period of up to 16 years The proposed research should help us better understand the biological link between lifestyle and clinical dementia and the role of NTF in both subclinical brain aging and in the development of AD. PUBLIC HEALTH RELEVANCE: Neurotrophic factors (NTF) are important in brain development, in memory formation, and for the survival and healthy functioning of adult and aging neurons;circulating levels increase with exercise and a frugal diet, so NTF may also be the biological link between a healthy body and mind. We propose to study variation in NTF pathway genes and serum NTF levels in a longitudinally-followed community of over 5000 middle-aged and elderly adults (the Framingham Original, Offspring and Omni cohorts), and relate these data to baseline and 5-year follow-up measures of brain MRI and cognitive performance, as well as to the risk of developing clinical dementia and Alzheimer's disease over a 16 year follow-up period. This study will improve our understanding of the role the NTF pathway plays in healthy and abnormal aging, perhaps leading to improved prevention and treatment strategies to combat cognitive aging and the development of Alzheimer's disease.